Socratech L.L.C. is a start-up company within the University of Rochester founded in July 2000 with a focus on vascular strategies for neurodegenerative disorders and Alzheimer's disease (AD). The goal of Phase I is to identify new therapeutic and diagnostic targets in AD neurovasculature/blood-brain barrier (BBB). Neurovasculature/BBB is comprised of brain endothelial cells (BEC), pericytes and astrocytes. Our central hypothesis is that AD could be primarily a neurovascular disorder and that dysfunctions in BEC, astrocytes and pericytes contribute significantly to the disease process. To optimize target assessment, we have developed a Process Biology approach which integrates several genomics and bioinformatics tools through different modules: the BioBank Socratech, BioAssay, Biolnfo, Microarray-Based Expression Profiling (MEP), Single-Target Expression Profiling (STEP), Histoproteomics and Rapid Inhibition of mRNA Expression (RIME). The BioBank Socratech with its 300 primary lines of BEC, pericytes, and glial cells from brains of AD patients and controls, tissue samples, RNA/DNA samples, RT-PCR primers and antibodies, is a central resource for this proposal. Our preliminary MEP/functional analysis of BEC and astrocytes supports the hypothesis that AD neurovascular cells are functionally and molecularly inherently different from controls and that they retain in culture certain pathoqenic molecular and cellular features observed in AD neurovasculature/BBB in brain tissue in situ. Phase I - Target Idenitification, will validate [unreadable] MEP/Functional data for selected Genes-of-Interest in AD and Controls through the STEP module by [unreadable] quantitative PCR in serial samples of cultured BEC and astrocytes, and in BEC and astrocytes isolated from brain tissue by Laser Capture Microscopy (aim 1); through the Histoproteomics module by immunodetection in serial brain tissues samples (aim 2); and will identify new Genes-of-Interest in pericytes by MEP (aim 3). [unreadable] [unreadable] Phase II will use STEP/RIME approach for Target Pathway Analysis and screening of different Libraries [unreadable] of Compounds, and Vectors for over-expression studies with drug-targetable genes. The Novelty is focus on the BBB in AD, and use of new in vitro neurovascular models in combination with LCM/QPCR tissue analysis to identify new targets. The potential products include new diagnostics DNA chips and brain imaging agents, therapeutic genetic vectors and new drugs to treat neurovascular AD disorder. [unreadable] [unreadable]